Photodefined aperture plate and method for producing the same

ABSTRACT

In one embodiment, a method for manufacturing an aperture plate includes depositing a releasable seed layer above a substrate, applying a first patterned photolithography mask above the releasable seed layer, the first patterned photolithography mask having a negative pattern to a desired aperture pattern, electroplating a first material above the exposed portions of the releasable seed layer and defined by the first mask, applying a second photolithography mask above the first material, the second photolithography mask having a negative pattern to a first cavity, electroplating a second material above the exposed portions of the first material and defined by the second mask, removing both masks, and etching the releasable seed layer to release the first material and the second material. The first and second material form an aperture plate for use in aerosolizing a liquid. Other aperture plates and methods of producing aperture plates are described according to other embodiments.

FIELD OF THE INVENTION

The present invention relates to liquid nebulizers, and moreparticularly, to an aperture plate for such liquid nebulizers capable ofaerosol delivery of liquid formulations having a controlled liquiddroplet size suitable for pulmonary drug delivery. The invention furtherrelates to the formation and use of aperture plates employed to producesuch aerosols.

BACKGROUND

In drug delivery applications, especially drug delivery to the pulmonarysystem of a patient, liquid nebulizers are advantageous in that they arecapable of delivering a fine mist of aerosol to a patient. A goal ofsuch nebulizer devices is to assure a consistent droplet size and/orflow rate and/or velocity of the expelled droplets to maximize deliveryto the targeted portion of the pulmonary system, such as the deep lung.

Some liquid nebulizers use a perforated plate, such as an aperture plate(AP), mesh plate, or vibrating plate, through which a liquid is forcedin order to deliver a fine mist of aerosol. In particular, vibratingmesh-type liquid nebulizers are advantageous over other types ofaerosolization devices, such as jet nebulizers or ultrasound nebulizers,in that they are capable of delivering a fine aerosol mist comprising adroplet size and droplet size range appropriate for pulmonary delivery,and can do so with relatively high efficiency and reliability. Suchvibrating mesh nebulizers can be advantageously small, do not requirelarge and/or external power sources, and do not introduce extraneousgases into a patient's pulmonary system.

Aperture plates manufactured for liquid drug pulmonary delivery areoften designed to have apertures sized to produce droplets (alsosometimes referred to as particles) of a size range from about 1-6 μm.Conveniently, the aperture plate may be provided with at least about1,000 apertures so that a volume of liquid in a range from about 4-30 μLmay be produced within a time of less than about one second. In thisway, a sufficient dosage may be aerosolized. An aperture size of theaperture plate of about 1-6 μm is useful because this particle sizerange provides a deposition profile of aerosol droplets into thepulmonary system. More particularly, a size range of about 1-4 μm isuseful because this particle size range provides a deposition profile ofaerosol droplets into the deep lung (comprising the bronchi andbronchioles, and sometimes referred to as the pulmonary region), with ahigher effective dose delivered, and concomitant therapeutic benefits. Aparticle size range larger than about 6 μm may decrease appropriatedispersal of the liquid into the pulmonary region of the lung.Therefore, providing an appropriate aperture size range, and controllingthe aperture size distribution, and thereby the size distribution ofliquid droplets, is a concern in this industry. Development of acost-efficient manufacturing process to consistently and reliablymanufacture aperture plates having the appropriate aperture sizes hasbeen a challenge for the electroforming technology typically used toproduce aperture plates.

Electroforming is a well established plating technology as it has beenwidely used in the inkjet printer industry. Such devices typically havelarge geometry apertures (about 10 μm or larger, in some examples). In atypical electroforming process, a metal forming process is used to formthin parts through electrodeposition onto a base form, referred to as amandrel. In a basic electroforming process, an electrolytic bath is usedto deposit an electroplatable metal onto a patterned conductive surface,such as metalized (i.e., deposited with a thin layer of metal) glass orstainless steel. Once the plated material has been built up to a desiredthickness, the electroformed part is stripped off the master substrate.This process affords adequate reproducibility of the master andtherefore permits production with good repeatability and process controlfor larger geometry (greater than about 10 μm) apertures. The mandrel isusually made of a conductive material, such as stainless steel. Theobject being electroformed may be a permanent part of the end product ormay be temporary, and removed later, leaving only the metal form, i.e.,“the electroform”.

The electroforming process is, however, disadvantageous in manyrespects. Electroforming is very susceptible to imperfections, anddefects at a mandrel surface (e.g., a supporting substrate surface)adversely affect the quality of a resultant aperture plate. As a result,high manufacturing yield and process consistency has remained elusive. Atypical aperture plate manufacturing yield is about 30%, and a 100%downstream assembly line inspection may be required because of processvariability.

A cross-sectional view of an electroformed aperture plate and a typicalprocess flow are shown in FIG. 1A and FIG. 1B, respectively, accordingto the prior art. Conventionally, as shown in FIG. 1A, an aperture plate102 is formed through three-dimensional growth of plating material on anarray of dome-shaped patterns 104 with a specific diameter and spacing.The dome pattern 104 is lithographically patterned, and then heattreated on a stainless steel mandrel. The dome-shaped structure 104 actsonly as an insulating layer for subsequent plating, precluding accurateand precise control of aperture geometry. The diameter and height of thedome-shaped structure 104 determines the approximate aperture 106 sizeand shape of aperture plates 102 produced through this process. Thespacing or pitch between the dome-shaped structures 104 is a factor indetermining the final aperture plate 102 thickness because the aperture106 size is determined by the plating time, that is, a longer platingtime results in a smaller aperture 106 size. As a result, the apertureplate hole density for a conventional, electroformed aperture plate 102is fixed for any given plate thickness. Because flow rate isproportional to the aperture plate aperture (or hole) density, the holedensity limitation of electroforming requires increasing the diameter ofthe aperture plate in order to deliver a higher flow rate. By “aperturedensity” it is meant the number of apertures per square unit of apertureplate, such as the number of apertures per mm². This has a significantlynegative impact on manufacturing costs and manufacturing yield, e.g.,the costs may be higher and yields may be lower. Moreover, particularlyin medical applications, it is often preferable to minimize the diameterof an aperture plate so that the entire device is as small as possible,both for positioning and space requirements, and to minimize powerconsumption.

Another limiting factor with the prior art electroforming process isaperture size control. As shown in FIGS. 2A-2D, to achieve a smalleraperture 202, the risk of aperture plate hole blockage increases greatly(due to a diffusion limiting factor near the tapered aperture area). Thethree-dimensional growth has both a linear horizontal growth r_(H) and alinear vertical growth r_(L). At a large aperture 202 size (typicallygreater than about 10 μm), there is approximately a linear relationshipbetween the horizontal growth r_(H) and the vertical growth r_(L) whichallows for the aperture 202 size to be relatively well controlled.However, once the aperture 202 size reaches a smaller dimension, thelinearity no longer holds, and controlling the aperture 202 size becomesdifficult. This non-linearity typically starts at aperture sizes ofabout 10 μm or smaller, such as smaller than about 9 μm or 8 μm or 7 μmor 6 μm. As can be seen in FIGS. 2A-2D, the longer the growth time, asindicated by the time (t) values in each figure, the thicker the layer204 becomes and the smaller the corresponding aperture 202 becomes.Because the thickness 204 and aperture 202 size are interrelated duringthe three-dimensional growth, plating conditions must be monitored andmodified during the plating process if the final desired aperture 202size is to be achieved, and this is not always successful. In somecases, as shown in FIG. 2D, the growth of the aperture plate may faildue to the layer being overgrown which causes the apertures 202 toclose. It is well known in the art that plating thickness 204 canfluctuate, sometimes by over 10%, across the plating layer due toinherent limits of this process technology. Again, this makes it verydifficult to control both the final aperture plate thickness 204 andaperture 202 size.

SUMMARY

According to one or more embodiments, a method for manufacturing anaperture plate includes depositing a releasable seed layer above asubstrate, applying a first patterned photolithography mask above thereleasable seed layer, the first patterned photolithography mask havinga negative pattern to a desired aperture pattern, electroplating a firstmaterial above the exposed portions of the releasable seed layer anddefined by the first mask, applying a second photolithography mask abovethe first material, the second photolithography mask having a negativepattern to a first cavity, electroplating a second material above theexposed portions of the first material and defined by the second mask,removing both masks, and etching the releasable seed layer to releasethe first material and the second material. The first material and thesecond material form an aperture plate for use in aerosolizing a liquid.

According to another embodiment, an aperture plate for use inaerosolizing a liquid includes a first material having a plurality ofapertures therein, the first material having a characteristic of beingformed through a photolithography process, a second material above thefirst material, the second material having a first cavity above theplurality of apertures in the first material, wherein the secondmaterial has a characteristic of being formed through a photolithographyprocess. The first material and the second material form an apertureplate.

In yet another embodiment, an aperture plate adapted for use inaerosolizing a liquid produced by a process which includes the steps of:a) depositing a releasable seed layer above a substrate, b) applying afirst patterned photolithography mask above the releasable seed layer,the first patterned photolithography mask having a negative pattern to adesired aperture pattern, c) electroplating a first material above theexposed portions of the releasable seed layer and defined by the firstmask to form a substantially planar structure having a plurality ofapertures therethrough, d) applying a second photolithography mask abovethe first material, the second photolithography mask having a negativepattern to a first cavity, wherein the first cavity is positioned abovethe plurality of apertures, e) electroplating a second material abovethe exposed portions of the first material and defined by the secondmask, f) removing both masks, and g) etching the releasable seed layerto release the first material and the second material.

Other aspects and embodiments of the present invention will becomeapparent from the following detailed description, which, when taken inconjunction with the drawings, illustrate by way of example theprinciples of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows a profile schematic of an aperture plate according to theprior art.

FIG. 1B shows a flowchart of a method of producing an aperture plateaccording to the prior art.

FIGS. 2A-2D show profile schematics during various stages of apertureplate growth, according to the prior art.

FIGS. 3A-3B show a cross-sectional view and a top view, respectively, ofan aperture plate, according to one embodiment.

FIGS. 4A-4B show a cross-sectional view and a top view, respectively, ofan aperture plate, according to one embodiment.

FIG. 5A shows a scanning electron microscope image of a top down view ofan aperture plate, according to one embodiment.

FIG. 5B shows a scanning electron microscope image of a top down view ofan aperture plate, according to one embodiment.

FIG. 6 shows a flowchart of a method of producing an aperture plateaccording to one embodiment.

FIGS. 7A-7L show various stages of formation of an aperture plateaccording to one embodiment.

FIG. 8A is a schematic cross-sectional representation of a nebulizerincluding an aperture plate, according to one embodiment.

FIG. 8B is a schematic cutaway cross-section detail of the nebulizershown in FIG. 8A, according to one embodiment.

DETAILED DESCRIPTION

The following description is made for the purpose of illustrating thegeneral principles of the present invention and is not meant to limitthe inventive concepts claimed herein. Further, particular featuresdescribed herein can be used in combination with other describedfeatures in each of the various possible combinations and permutations.

Unless otherwise specifically defined herein, all terms are to be giventheir broadest possible interpretation including meanings implied fromthe specification as well as meanings understood by those skilled in theart and/or as defined in dictionaries, treatises, etc.

As used herein, the term “liquid” may refer to a single phase solution,a multiple phase solution, an emulsion or nanosuspension.

As used herein the term “cylinder” (and “cylindrical”) refer to ageometric figure comprising a section of a right circular cylinder;however, unless clear from the context, other cross sectional shapes maycomprise the cylinders referred to herein. Moreover, the radius of thecylinder does not necessarily have to be uniform throughout thecylindrical shape, but may, in some embodiments, vary such as from topto bottom to result in some degree of taper.

It must also be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralunless otherwise specified.

According to one general embodiment, a method for manufacturing anaperture plate includes depositing a releasable seed layer above asubstrate, applying a first patterned photolithography mask above thereleasable seed layer, the first patterned photolithography mask havinga negative pattern to a desired aperture pattern, electroplating a firstmaterial above the exposed portions of the releasable seed layer anddefined by the first mask, applying a second photolithography mask abovethe first material, the second photolithography mask having a negativepattern to a first cavity, electroplating a second material above theexposed portions of the first material and defined by the second mask,removing both masks, and etching the releasable seed layer to releasethe first material and the second material. The first material and thesecond material form an aperture plate for use in aerosolizing a liquid.

According to another general embodiment, an aperture plate for use inaerosolizing a liquid includes a first material having a plurality ofapertures therein, the first material having a characteristic of beingformed through a photolithography process, a second material above thefirst material, the second material having a first cavity above theplurality of apertures in the first material, wherein the secondmaterial has a characteristic of being formed through a photolithographyprocess. The first material and the second material form an apertureplate.

In yet another general embodiment, an aperture plate adapted for use inaerosolizing a liquid produced by a process which includes the steps of:a) depositing a releasable seed layer above a substrate, b) applying afirst patterned photolithography mask above the releasable seed layer,the first patterned photolithography mask having a negative pattern to adesired aperture pattern, c) electroplating a first material above theexposed portions of the releasable seed layer and defined by the firstmask to form a substantially planar structure having a plurality ofapertures therethrough, d) applying a second photolithography mask abovethe first material, the second photolithography mask having a negativepattern to a first cavity, wherein the first cavity is positioned abovethe plurality of apertures, e) electroplating a second material abovethe exposed portions of the first material and defined by the secondmask, f) removing both masks, and g) etching the releasable seed layerto release the first material and the second material.

According to one or more embodiments, a process for making apertureplates with a precisely defined aperture size and shape to meet aspecified droplet size and droplet size distribution is presented.Moreover, the photo-defined approach of the present invention permitsdecoupling of flow rate from the droplet size and/or size distribution.Hence, the present invention allows for aperture plate productionwherein flow rate and droplet size and/or size distribution may beaddressed and controlled independently of one another, which is anothersignificant advantage over the prior art. In addition, embodimentsdescribed herein provide scalability capable of large-volumemanufacturing by removing costly, labor-intensive manual process steps(e.g., manual harvesting and punching) from the manufacturing processes.Prior art methods use a manual process named “harvesting” to peel afinal plated material off a supporting substrate (e.g., mandrel) andthen punch sheet material into a desired diameter to be used as apertureplates.

According to one or more embodiments, a method for manufacturing anaperture plate, mesh, perforated plate, etc., for a liquid nebulizer,such as a vibrating mesh nebulizer comprises a photolithography process,which affords precise aperture size definition and control. Thisphotolithography method of making aperture plates may, in one or moreembodiments, provide a parametrically-controlled aperture plate to meetdesired specifications for delivery of a wide variety of liquid deliveryapplications, such as delivery of aerosolized drug formulations.Furthermore, the photo-defined process has a significant potential tomarkedly improve process yield and thus offers a significant potentialto lower manufacturing cost.

According to some embodiments, semiconductor process techniques may beapplied to the method of manufacturing of the present invention toenable a fully automatable process flow for the manufacturing ofaperture plates through photomask design. Also, instead of being limitedto stainless steel substrates, a more conventional silicon wafer may beused, along with a convenient release process utilizing a release layerand an etching process to remove the release layer, such as a wetetching release process.

Now referring to FIGS. 3A-3B, a cross-sectional view and top view of anaperture plate 300 formed through a photolithography process are shownaccording to one embodiment. As can be seen in FIG. 3A, the apertureplate 300 includes a plurality of apertures 302, a cavity 304, andsidewalls 306. The aperture plate 300 is used for aerosolizing a liquid,according to preferred embodiments. The aperture plate 300 comprises afirst material 308 having a plurality of apertures 302 therein. Thefirst material 308 is a layer having a thickness Φ₃ the same as a heightof the apertures 302. The first material 308 has one or morecharacteristics resulting from formation through a photolithographyprocess, such as a smooth surface, well controlled diameters (Φ₁, Φ₄)and pitch (Φ₅), uniform dimensions, etc. The aperture plate 300 alsocomprises a second material 310 (which may comprise the same material ora different material than the first material 308) which is positioneddirectly or indirectly above the first material 308, such that the firstmaterial 308 may form the apertures 302 and the second material 310 maydefine the cavity 304 and form the sidewalls 306. The cavity 304 definedby the second material 310 is positioned above the plurality ofapertures 302 in the first material 308. The second material 310 is alayer having a thickness the same as a depth of the cavity 304, e.g.,Φ₂-Φ₃. The second material 310 also has one or more characteristicsresulting from formation through a photolithography process, asdescribed previously.

In one approach, each of the plurality of apertures 302 of the firstmaterial 308 may have a diameter Φ₄ of between about 1 μm and about 5μm. In another approach, a thickness ψ₃ of the first material 308 nearthe plurality of apertures 302 may be between about 5 μm and about 10μm.

As shown in FIG. 3A, in one embodiment, a height Φ₂ of the sidewalls 306may be between about 40 μm and about 80 μm, such as about 60 μm, 65 μm,etc. In another embodiment, a width Φ₁ of the cavity 304 may be betweenabout 50 μm and 80 μm, such as about 60 μm, 65 μm, etc. In preferredembodiments, the height Φ₂ of the sidewalls 306 may correspond to thewidth Φ₁ of the cavity 304. In one or more embodiments, the pitch Φ₅ (adistance measured between apertures) of one or more of the apertures 302may be between about 2 μm to 20 μm, or about 4 μm to 10 μm, or any valueor range in between. In some embodiments, the selection of the pitchimpacts or effects flow rate, and/or mechanical strength of the apertureplate. In some embodiments, selection of pitch is a function ofmechanical considerations, such as vibration frequency.

Referring now to FIG. 3B, a top view of the aperture plate 300 is shown,according to one embodiment, taken from Line 3B in FIG. 3A. Referringagain to FIG. 3B, an aperture pattern is shown having a star shape, butany shape or configuration may be used as desired, such as circular,square, triangular, or free-form, etc. The process of the presentinvention permits forming into the aperture plate 300 a significantlylarger number of apertures 302 than which may be formed into an apertureplate according to the prior art. This is due to the process describedherein according to various embodiments which allows more freedom andprecision in defining aperture patterns, aperture density, apertureshape and aperture size as desired to achieve the desired liquiddelivery results. Moreover, embodiments described herein may make use ofa greater percentage of an aperture plate area, because the aperturesize is not dependent upon an aperture plate thickness. In other words,the thickness is decoupled from the aperture size, in contrast toaperture plates produced through prior art electroforming, in which thethickness of the aperture plate is interrelated to the size of theapertures. Therefore, more apertures 302 per unit of aperture plate areaare possible, with a potential benefit of greater throughput whilemaintaining control of particle size and/or particle size distribution.In some embodiments, the number of apertures 302 may range from about 1aperture to about 1000 apertures per mm². For a typically-sized apertureplate (i.e., 20 mm²) for pulmonary delivery of a nebulized liquid drug,the number of apertures may range from about 50 to about 25,000, orabout 300 to about 10,000, or any number range or value therebetween.FIG. 3B illustrates a configuration wherein 10,000 or more apertures maybe formed. In one embodiment of a nebulizer device, having about a 20mm² aperture plate, apertures may number from 500 to 5,000, for examplefrom 1,000 to 3,000, or any range or value therebetween. While there isno practical lower limit to the number of apertures (e.g., one is theminimum) which may be formed into an aperture plate, the process of thepresent invention permits a greatly increased number, such as 500 or1,000 or more per mm².

In one or more embodiments, the aperture exit opening (also referred toas an outlet) may have a diameter in a range from about 0.5 μm to about10 μm, and in some embodiments it may range from about 1 μm to about 6μm, about 1 μm to about 4 μm, about 1 μm to about 3 μm in diameter,etc., or any range or value therebetween. A distribution of aperturesizes may range from any desired smallest size to any desired largestsize, and there is no required standard deviation between aperturesizes, according to various embodiments. The process described above, inone embodiment, advantageously permits better control over aperture sizethan prior art processes, thus aperture plates may be reliably andrepeatably produced with very small exit openings of the apertures, suchas 0.5 μm, 0.4 μm, 0.3 μm, 0.2 μm, 0.1 μm, etc. In addition, accordingto embodiments presented herein, the process is capable of bettercontrol precision in achieving the desired aperture size, andconsequently, a more tightly controlled range, i.e., a sharperdistribution curve. It is to be noted, however, that embodimentspresented herein also provide for an aperture plate wherein aperturesmay purposefully be formed to have sizes different from one another,such as a set of 3 μm apertures and a set of 1 μm apertures in the sameaperture plate.

According to embodiments of the present invention, the diameter Φ₄ ofthe apertures 302, the height Φ₂ of the sidewalls 306, the thickness <₃of the first material 308 near the plurality of apertures 302, the widthΦ₁ of the cavity 304, and/or the pitch Φ₅ may be independentlycontrolled, such as to provide a desired flow rate, droplet size anddroplet size distribution, when aerosolizing a liquid through theapertures 302.

According to some embodiments, the first material 308 and/or the secondmaterial 310 may include any suitable material, such as at least one ofNi, Co, Pd, Pt, alloys thereof, and mixtures thereof, among othersuitable materials. A suitable material may be any electroplatablematerial, and in some further embodiments, the material chosen may havea resistance to chemical properties of a liquid to be aerosolized withthe aperture plate 300.

Now referring to FIGS. 4A-4B, a cross-sectional view and top view of anaperture plate 400 formed through a photolithography process are shownaccording to one embodiment. As can be seen in FIG. 4A, the apertureplate 400 includes a plurality of apertures 402, a first cavity 404, asecond cavity 408, and sidewalls 406. The aperture plate 400 may be usedfor aerosolizing a liquid, according to preferred embodiments.

The aperture plate 400 includes a first material having a plurality ofapertures 402 therein. The first material 410 is a layer having athickness Φ_(c) the same as a height of the apertures 402. The firstmaterial 410 has a characteristic of being formed through aphotolithography process, such as smooth surfaces, uniform growth, etc.,as described previously. The aperture plate 400 also includes a secondmaterial 412 (which may be the same material or a different materialthan the first material 410) which is positioned directly or indirectlyabove the first material 410, the second material 412 having a firstcavity 404 above the plurality of apertures 402 in the first material410. The second material 412 is a layer having a thickness the same as adepth Φ_(e) of the first cavity 404. The second material 412 also has acharacteristic of being formed through a photolithography process asdescribed previously, which results in one or more beneficial propertiesof smooth surfaces, well controlled diameters (Φ_(a), Φ_(d), Φ_(f)) andpitch (Φ_(g)), uniform dimensions, etc.

The aperture plate 400 also includes a third material 414 having asecond cavity 408, the third material 414 being positioned above thesecond material 412 such that the cavities 404 and 408 are positionedabove one another. The third material 414 is a layer having a thicknesswhich is the same as a depth of the second cavity 408, e.g.,Φ_(b)−(Φ_(c)−Φ_(e)). The third material 414 has a characteristic ofbeing formed through a photolithography process as described previously,the second cavity 408 is above the first cavity 404, and an internaldiameter Φ_(a) of the second cavity 408 is greater than an internaldiameter Φ_(f) of the first cavity 404.

In one approach, each of the plurality of apertures 402 of the firstmaterial 410 may have a diameter Φ_(d) of between about 1 μm and about 5μm. In another approach, a thickness Φ_(c) of the first material 410near the plurality of apertures 402 may be between about 5 μm and about10 μm, such as about 6 μm.

As shown in FIG. 4A, in one embodiment, a height Φ_(b) of the sidewalls406 may be between about 40 μm and about 80 μm, such as about 60 μm, 65μm, etc. In another embodiment, a width Φ_(f) of the first cavity 404may be between about 20 μm and 30 μm, such as about 25 μm. In anotherembodiment, a depth Φ_(e) of the first cavity 404 may be between about20 μm and 30 μm, such as about 25 μm. In preferred embodiments, theheight Φ_(b) of the sidewalls 406 may correspond to the width Φ_(f) ofthe first cavity 404 and/or second cavity.

Referring now to FIG. 4B, a top view of the aperture plate 400 is shown,according to one embodiment, taken from Line 4B in FIG. 4A. Referringagain to FIG. 4B, an aperture pattern is shown having three apertures402, but any shape and any number of apertures 402 may be produced, asdesired. According to preferred embodiments, the diameter Φ_(d) of theapertures 402, the height Φzb of the sidewalls 406, the thickness Φ_(c)of the first material 410 near the plurality of apertures 402, the widthΦ_(a) of the second cavity 408, the width Φ_(f) of the first cavity 404,and the pitch Φ_(g) may each be controlled independently of one another,such as to provide a desired flowrate and droplet size when aerosolizinga liquid through the apertures 402.

According to some embodiments, the first material 410, the secondmaterial 412, and/or the third material 414 may comprise any suitablematerial. In some embodiments, the materials may suitably be selectedfrom the platinum metals group. In some embodiments, the materialscomprise at least one of Ni, Co, Pd, Pt, alloys thereof, and mixturesthereof, among other suitable materials. The aperture plate 400 may beconstructed of a high strength and/or a corrosion resistant material. Asone example, the plate body (e.g., the first material 410, the secondmaterial 412, and/or the third material 414) may be constructed frompalladium or a palladium nickel alloy. Palladium or a palladium nickelalloy are corrosion resistant to many corrosive materials, particularlysolutions for treating respiratory diseases by inhalation therapy, suchas an albuterol sulfate or an ipratroprium solution, which may be usedin medical applications. In some embodiments, at least one of the first,second and/or third material have a low modulus of elasticity, and canresult in a lower stress for a given oscillation amplitude. Othermaterials that may be used to construct the plate body include stainlesssteel, stainless steel alloys, gold, gold alloys, and the like. Asuitable material may be any electroplatable material, and in somefurther embodiments, the material chosen may be inert to, and/or have achemical resistance to, an aerosolized liquid to be used with theaperture plate 400.

The apertures of the aperture plates in any one embodiment may have anexit opening having a diameter anywhere within a range from about 0.5 μmto about 6 μm, to produce droplets that are about 0.5 μm to about 6 m insize. In other embodiments, the aperture exit opening (also referred toas an outlet) may have a diameter of from about 1 μm to about 4 μm,about 1 μm to about 3 μm, etc., or any range or value therebetween, toproduce droplets of about a corresponding size. Generally, droplet sizeis approximately equal to outlet size, however exiting droplets may formand become slightly larger or smaller, depending upon thecharacteristics, such as the surface tension and/or rheologicalproperties, of the liquid being aerosolized. Exit opening is used hereinto mean the opening from which the droplet emerges, and which may alsobe considered as downstream, or distal, to the liquid supply. This iscontrasted with the inlet opening, also referred to as a liquid supplyopening, which is the opening in contact with, or proximal to, thesupply of liquid to be aerosolized. The liquid supply opening is thuslarger in diameter and/or area than the exit opening. In someembodiments, the liquid supply opening may range in size from about 20μm to about 200 μm in diameter including any range or valuetherebetween.

In one or more embodiments, the apertures may be formed (as shown, forexample, in FIG. 3B and/or 4B) to describe a series of concentric,stepped-down cylinders within the aperture plate (as viewed from theinlet opening to exit opening). In some embodiments, the apertures maybe formed to describe within the aperture plate two concentriccylinders, as shown in FIG. 3B. In such embodiments, the liquid inletopening may be from about 20 μm to about 100 μm in diameter, and theexit opening may be from about 0.5 μm to about 6 μm in diameter. In someembodiments, the exit opening diameter may be about 1% to about 10% ofthe inlet opening diameter. More particularly, in one or moreembodiments, an inlet opening may comprise a diameter from about 50 μmto about 80 μm, and an exit opening may comprise a diameter of fromabout 1 μm to about 4 μm.

In one or more embodiments, apertures may be formed into the apertureplate as three concentric cylinders, as shown in FIG. 4B. According toone or more embodiments, three or more concentric cylinders may be usedto form within the aperture plate to describe the aperture(s). In suchembodiments, the apertures comprise a cylindrical inlet opening, one ormore intermediate cylindrical openings, and one or more cylindrical exitopenings formed into the aperture plate. These openings may havediameters comprising anywhere from about 50 μm to about 200 μm for theinlet, about 10 μm to about 40 μm for the intermediate opening, andabout 1 μm to about 5 μm for the exit opening. In should be noted thatthe concentric cylinder arrangement of openings does not necessarilyrequire that the openings be coaxial. In some embodiments, asillustrated for example, in FIGS. 3 , a plurality (two or more) of exitopenings may be formed within the diameter of the larger inlet opening.Thus, multiple apertures 302 (the exit openings) are typically formedwithin the area circumscribed by aperture 304 (the inlet opening). Theseexit openings may be formed in a variety of patterns, configurations,and positions relative to an axis of the larger opening. While generallya straight-sided aperture is obtained, some angle in the side walls ofthe aperture may occur due to light attenuation in the lithographyprocess. This angle tends to be more pronounced as aperture sizedecreases. Generally, an angle of the side walls of a given aperturedoes not adversely impact droplet ejection performance, and may in someembodiments, be beneficial.

In some embodiments described herein, the apertures generally describein the aperture plate an inverted ziggurat shape. In particular, whenreferring to the embodiment described by FIGS. 4 , the ziggurat shape isnotable. The ziggurat shape may be used to provide mechanical strengthto the aperture plate, such that the aperture plate is capable of beingused in a vibrating mesh type nebulizer and can withstand the forcesexerted on the aperture plate due to the vibrating. The shape of theaperture plate (e.g., ziggurat shape) is not necessarily used to providea particular size, or size distribution of the resulting droplets.

Conveniently, the aperture plates described herein according to variousembodiments may be formed in a shape of a dome (although otherconfigurations, such as planar and near-planar, are suitable) asdescribed generally in U.S. Pat. No. 5,758,637, previously incorporatedby reference. Typically, the aperture plate will be vibrated at afrequency in a range from about 45 kHz to about 200 kHz whenaerosolizing a liquid. Further, when aerosolizing a liquid, the liquidmay be placed into contact with a rear surface of the aperture platewhere the liquid adheres to the rear surface by surface tension forces.Upon vibration of the aperture plate, liquid droplets are ejected fromthe front surface as described generally in U.S. Pat. Nos. 5,164,740;5,586,550, and 5,758,637, previously incorporated by reference.

Now referring to FIG. 6 , a method 600 for manufacturing an apertureplate is shown according to one embodiment. The method 600 may becarried out in any desired environment, and may include more or feweroperations than those shown in FIG. 6 , according to variousembodiments.

In operation 602, a releasable seed layer is deposited above asubstrate. The releasable seed layer may preferably comprise an etchablematerial, such as a metal, for example a conductive metal. In someembodiments, the metal is one or more of: Al, Cu, Si, Ni, Au, Ag, steel,Zn, Pd, Pt, etc., alloys thereof such as brass, stainless steel, etc.,mixtures of the foregoing, and the like. In some embodiments, thereleasable seed layer may comprise an etchable conductive material, suchas conductive metals like Au, Ti, Cu, Ag, etc., and alloys thereof. Ofcourse, any other material may be used for the releasable seed layer aswould be understood by one of skill in the art upon reading the presentdescriptions.

In operation 604, a first patterned photolithography mask is appliedabove the releasable seed layer. The first patterned photolithographymask has a negative pattern to a desired aperture pattern.

The aperture size may be defined precisely through the patterns of thephotolithography mask (photo dots) made through the photolithographyprocess. As compared to prior art methods which use an electroformingprocess, the aperture is formed through a three-dimensional growth ofplating materials.

In one approach, the first patterned photolithography mask may impartapertures to the first material having a diameter of between about 0.5μm and about 6 μm.

In operation 606, a first material is electroplated above the exposedportions of the releasable seed layer and defined by the first mask. Inone approach, the first material near the apertures may be formed to athickness that is independent of a diameter of the apertures, such asbetween about 5 μm and about 10 μm, according to some embodiments.

The height of the first patterned photolithography mask and thethickness of the first material near the apertures are factors indetermining the performance of the aperture plate after formation iscomplete. FIG. 5A shows a scanning electron microscope (SEM) image of atop down view of an internal side of an aperture from an aperture plateproduced through methods described herein. As can be seen, the edges ofthis aperture are smooth and the shape is substantially uniform. Theaperture shown in FIG. 5A was produced by plating the first material toa thickness that was less than the height of the first patternedphotolithography mask, thereby ensuring that the material was depositeduniformly.

Now referring to FIG. 5B, which is a SEM image of a top down view of aninternal side of an aperture plate produced through methods describedherein, some advantages of the methods are noticeable. The apertures inthis aperture plate were produced in the same way as the aperture inFIG. 5A. The aperture plate shown in FIG. 5B has three planar surfaces,with each innermost surface being recessed from the next closestoutermost surface, similar to the aperture plate shown in FIGS. 4A-4B.Referring again to FIG. 5B, it can be seen that the apertures areprecisely controlled in placement and size, and the aperture plate hassubstantially vertical and substantially smooth walls. This precisemanufacturing ability is an advantage to the methods described herein,according to various embodiments, when compared to conventionalmanufacturing methods, such as electroforming.

In some embodiments, the diameter of the apertures and the pitch of theapertures may be chosen (dependently or independently) such that thethickness of the first material near the apertures and a flow-rate ofthe aerosolized liquid through the apertures is controlled to achieve adesired value or range.

In another embodiment, a thickness of the first material near theapertures may be independent of a placement density of the apertures inthe aperture pattern.

In operation 608, a second photolithography mask is applied above thefirst material. The second photolithography mask has a negative patternto a first cavity.

In operation 610, a second material is electroplated above the exposedportions of the first material and defined by the second mask.

In one approach, the first material and the second material may be thesame material. In another approach, the first material and the secondmaterial may comprise an electroplatable material having a resistance toan aerosolized liquid.

In operation 612, both masks are removed through any technique known inthe art. In one embodiment, both masks are removed in a single step,e.g., they are removed at the same time.

In operation 614, the releasable seed layer is etched to release theplated materials. A preferred etching includes a wet etch process, amongother methods of removing the release layer.

In one embodiment, the method 600 may include more operations, such asthose described below.

In one optional operation, a third photolithography mask may be appliedabove the second material, the third photolithography mask having anegative pattern to a second cavity. This third photolithography maskmay be applied prior to removing the first and second mask. Then, athird material may be electroplated above the exposed portions of thesecond material, and defined by the third mask. All masks may be removedafter the completion of electroplating. The second cavity may be abovethe first cavity and an internal diameter of the second cavity may begreater than an internal diameter of the first cavity.

According to some embodiments, the first material, the second material,and/or the third material may comprise any suitable material. In someembodiments, the materials may suitably be selected from the platinumgroup. In some embodiments the materials comprise at least one of Ni,Co, Pd, Pt, and alloys thereof, among other suitable materials. Thefirst material, the second material, and/or the third material maycomprise a high strength and corrosion resistant material, in oneembodiment. As one example, the first material, the second material,and/or the third material may comprise a palladium nickel alloy. Such analloy is resistant to many corrosive materials, particularly solutionsfor treating respiratory diseases by inhalation therapy, such as analbuterol sulfate or ipratroprium solution, which may be used in medicalapplications. Further, the palladium nickel alloy has a low modulus ofelasticity and therefore a lower stress for a given oscillationamplitude. Other materials that may be used for the first material, thesecond material, and/or the third material include palladium, palladiumnickel alloys, stainless steel, stainless steel alloys, gold, goldalloys, and the like.

To enhance the rate of droplet production while maintaining the dropletswithin a specified size range, the apertures may be constructed to havea certain shape. In one or more embodiments, the apertures may be formedto describe in the aperture plate a ziggurat shape. Using this approach,aperture plates may be formed as a series of concentric, stepped downcylinders (as viewed from the inlet side to exit opening). In someembodiments, the aperture plates may be formed as two concentriccylinders. In such embodiments, the liquid inlet may be from about 50 μmto about 100 μm, and the exit opening may be from about 0.5 μm to about6 μm. More particularly, in one embodiment, an inlet opening maycomprise a diameter from about 60 μm to about 80 μm, and an exit openingmay comprise a diameter from about 1 μm to about 4 μm.

According to one or more embodiments, aperture plates may be formed asthree or more concentric cylinders. In such embodiments, there is aninlet cylinder, one or more intermediate cylinders, and an exit platehaving outlets formed therein. In some embodiments, the exit openingdiameter for the outlets formed therein may be about 1% to about 50% ofthe inlet opening diameter. In some embodiments, the next smalleropening diameter may be about 10% to about 30% of the next largeropening diameter. For example, the diameters may comprise anywhere fromabout 50 μm to about 100 μm for the inlet, about 10 μm to about 30 μmfor the intermediate, and about 1 μm to about 5 μm for the exit. In anyof the foregoing, the apertures describe in the aperture plate aninverted ziggurat shape. Such a shape provides for a robust apertureplate, and may provide flow rate benefits, such as increased flow ratewhile maintaining droplet size. In this way, the aperture plate may findparticular use with inhalation drug delivery applications. It is also tobe noted that the aperture walls are described as generallystraight-sided, that is, the aperture walls describe a section of aright circular cylinder geometric shape. In other word, the aperturewalls are typically perpendicular to a plane of the aperture plate, orto a tangent to a dome-shaped aperture plate. In some embodiments,however, the aperture walls may possess some angle, and/or may even takeon a conical cross-section.

According to one approach, the aperture plate may be formed in a fullyautomated process, which does not require manual stamping procedures.

Now referring to FIGS. 7A-7L, the method is described schematically.

In FIGS. 7A-7B, a releasable seed layer 704 is deposited above asubstrate 702. In preferred embodiments, the substrate 702 may compriseSi, and the releasable seed layer 704 may include any etchableconductive metal.

In FIGS. 7C-7E, a first patterned photolithography mask 710 is appliedabove the releasable seed layer 704. The first patternedphotolithography mask 710 has a negative pattern to a desired aperturepattern, and may be formed by spin coating photoresist 706, applying aphotomask 708 having a desired pattern to expose removed portions of thephotoresist 706, and dissolving the exposed portions through any methodknown in the art, such as by use of a developer known in the art, thuslycreating the first mask 710.

In FIG. 7F, a first material 712 is electroplated above the exposedportions of the releasable seed layer 704 and the patterns are definedby the first mask.

In FIGS. 7G-7I, a second photolithography mask 714 is applied above thefirst material 712. The second photolithography mask 714 has a negativepattern to a first cavity. The second photolithography mask 714 may beformed by spin coating photoresist 716, applying a photomask 718 havinga desired pattern, exposing removed portions of the photoresist 716, anddissolving the exposed portions through any method known in the art,such as by use of a developer known in the art, thusly producing thesecond mask 714.

In FIG. 7J, a second material 720 is electroplated above the exposedportions of the first material 712 and the patterns are defined by thesecond mask. Then, the second mask 714 and the first mask 710 areremoved through any technique known in the art, resulting in a structureas shown in FIG. 7K. Then, the releasable seed layer 704 is etched torelease both the first material 712 and the second material 714,resulting in a structure as shown in FIG. 7L. A preferred etchingincludes a wet etch process. Other etching processes which may besuitable methods of removing the release layer include plasma etchingand photochemical etching.

In preferred embodiments, the first material and the second material mayform an aperture plate for use in aerosolizing a liquid in a vibratingmesh nebulizer. In these embodiments, the photo-defined approach permitscontrol of flowrate independently of the droplet size because theaperture size and aperture pattern density may be independentlycontrolled.

For example, the flowrate of a liquid aerosol generator is expected tobe proportional to total aperture numbers (which when combined with thesize of each aperture results in total aperture area). This is anothersignificant advantage over the prior art where the aperture patterndensity is limited by a required plating thickness. As a result, themethods disclosed herein of making aperture plates may provide aparametrically controlled aperture plate to meet desired specificationsfor delivery of a wide variety of liquid drug formulations.

According to one embodiment, an aperture plate produced through methodsdescribed herein may include apertures of various sizes, variousdomains, various shapes, various profiles, various geometries, etc. Forexample, an aperture plate may comprise one or more domains comprising aplurality of apertures arranged in a circular pattern, together with oneor more domains comprising a plurality of apertures arranged in anon-circular, such as elliptical, triangular, or quadrilateral pattern.The apertures in the different domains may have varying or identicalareas, such as varying diameters of between about 1 μm to about 5 μm.

The apertures further may comprise an even dispersion about the area ofthe aperture plate, an uneven dispersion, or may be both evenly andunevenly dispersed, such as in different domains. In another embodiment,an aperture plate may include apertures having a first domain in aninner portion and apertures having a second domain in an outer portion.Moreover, the photolithographic process described herein allowsproduction of the aperture plate itself in varying patterns orgeometries. Thus, aperture plates can be readily formed to be circular,elliptical, square and/or star-shaped, for example. Tabs or projectionsmay be formed onto the aperture plate to assist in manufacturing anebulizer therewith, in some embodiments. Of course, any otherarrangement of apertures, aperture sizes, aperture domains, apertureprofiles, etc., may be produced using the methods described herein, aswould be understood by one of skill in the art upon reading the presentdescriptions.

The methods disclosed herein do not require a stringent alignmenttolerance between layers because of the displacement of the two or morelayers provides a good alignment margin. Additional advantages over theelectroforming process of making aperture plates include that thephoto-defined aperture size is not related to the plating thickness.Therefore, using a photo-defined process enables improved processcontrol and a potential for improved manufacturing yield. The dependenceof aperture size on plating thickness has been a significant factor inyield loss for conventional electroforming processes, which can now beavoided using techniques described herein. Also, multi-layer processescan be used to achieve a final desired aperture plate geometry, whichwas not possible using conventional aperture plate formation techniques.

Aperture plates have been built using the processes described herein,and aerosol testing data from these aperture plates appear below inTable 1 for performance comparison. Table 1 shows test results of threephoto-defined aperture plates according to embodiments herein and threeelectroformed aperture plates according to the prior art.

TABLE 1 TCAG # Type VMD (μm) GSD Span P35 Photo-defined 2.6 1.5 1.3 P42Photo-defined 2.5 1.5 1.3 P43 Photo-defined 2.2 1.5 1.2 AvgPhoto-defined 2.4 1.5 1.3 F007 Electroforming 4.2 1.9 1.7 F038Electroforming 4.0 1.8 1.7 F044 Electroforming 4.4 1.8 1.7 AvgElectroforming 4.2 1.8 1.7

In Table 1, TCAG indicates which sample of a tube core aerosol generatorwas tested, VMD indicates a volume median diameter which is determinedbased on the size of the droplets exiting the aperture plate, GSDindicates a geometric standard distribution and is the calculation of(D₈₄/D₅₀), and Span indicates the span of the calculation of(D₉₀−D₁₀)/D₅₀, where D is a droplet size at the percentile (as indicatedby the subscript numbering) of the droplet size distribution which wasmeasured by light scattering technology, such as a Malvern lightscattering instrument. For example, for a photo-defined unit P35, thelight scattering method measures D₁₀=1.414 μm, D₅₀=2.607 μm, D₈₄=4.038μm, D₉₀=4.844 μm, so the GSD=D₈₄/D₅₀=1.549. For an electroformed unitF007, the light scattering method measures D₁₀=1.585 μm, D₅₀=4.245 μm,D₈₄=8.052 μm, D₉₀=8.935 μm, so the GSD=D₈₄/D₅₀=1.897.

By way of comparison, the droplet size distribution for photo-definedunits is 79% narrower than that for electroformed ones when assuming thesame value of D₅₀, which indicates better controlled droplet size ofaerosolized medicine and more effective dosage delivered into the lung.

As can be seen from Table 1, the aperture plates produced throughmethods described herein (P35, P42, P43) have a smaller GSD thanconventionally produced (prior art) aperture plates (F007, F038, F044).A smaller droplet size (near 1-2 μm) is considered very desirable totarget deep lung delivery. A smaller GSD corresponds to a narrowerdistribution of droplet size produced by the aperture plate, which is adesirable characteristic for effective targeted delivery into the lung.

The units tested and tabulated in Table 1 are “hybrid” aperture plates.Here, the “hybrid” means that the apertures and aperture plate geometryare defined through photolithographic process but aperture plates aremade on stainless steel substrates and harvested from the substrateinstead of Si or some other substrate material.

The first prototype made through methods described herein showspromising results. It delivers up to a 1.2 mL/min flowrate at a mediandroplet size of 3.3 μm. For comparison, a typical electroformed apertureplate device delivers only 0.3 mL/min flowrate at a larger mediandroplet size of 4.6 μm. The photo-defined aperture plate is also capableof delivering an even smaller droplet size, about 2.7 μm at a flow rateof 0.4 mL/min. This is a significant improvement over an aperture platemanufactured using a prior art electroforming process. Markedimprovement is achieved in delivery of smaller droplet sizes in VMD andin achieving a narrower size distribution, e.g., GSD and Span forphoto-defined aperture plates vs. electroformed ones. A furtherimprovement in aperture size, aperture shape, and/or size distributioncontrol is expected with fully photo-defined processes, in whichstainless steel substrates are replaced with high quality Si substrates.Thus, a more precisely controlled aperture size may be achieved from thephotolithographic process of the present invention than are shown in theresults of Table 1.

Aperture plates may be constructed so that a volume of liquid in a rangefrom about 4 μL to about 30 μL may be aerosolized within a time durationof less than about one second by using an aperture plate having about1000 apertures, according to some embodiments. Further, the droplet sizeand droplet size distribution resulting from aerosolization through theaperture plate of the present invention may result in a respirablefraction (e.g. that fraction of droplets which reach the deep lung) thatis greater than about 40% or 50% or 60%, 70% or 80% or 90% or 95% or 98%or 99% in many embodiments. In one or more embodiments, this respirablefraction is achieved by using the aperture plate of the presentinvention with a piezo-actuated, vibrating mesh type nebulizer, such asthose described in U.S. Pat. Nos. 5,164,740, 5,586,550, and 5,758,637,previously incorporated by reference. In this way, a medicament may beaerosolized and then efficiently inhaled by a patient.

Now referring to FIGS. 8A-8B, a vibrating mesh type nebulizer is shownaccording to one embodiment. As shown in FIG. 8A, an aperture plate 800may be configured to have a curvature, as in a dome shape, which may bespherical, parabolic or any other curvature. Of course, in otherembodiments, the aperture plate 800 may be substantially planar, and isnot limited to the arrangement shown in FIGS. 8A-8B. The aperture plate800 may be formed to have a dome portion 808 over its majority, and thismay be concentric with the center of the aperture plate 800, thusleaving a portion of the aperture plate 800 that is a substantiallyplanar peripheral ring portion 812. The aperture plate 800 may have afirst face 804 and a second face 806. As shown in FIG. 8B, the apertureplate 800 may also have a plurality of apertures 814 therethrough. Thefirst face 804 may comprise a concave side of the dome portion 808 andthe second face 806 may comprise a convex side of the dome portion 808of the aperture plate 800. The apertures 814 may be tapered to have awide portion at the inlet 810 at the first face 804 and a narrow portionat the outlet 816 at the second face 806 of the aperture plate 800, ormay be substantially straight from inlet 810 to outlet 816.

Typically, a liquid is placed at the first face 804 (also referred to asthe liquid supply side) of the aperture plate 800, where it can be drawninto the inlet 810 of the apertures 814 and emitted as an aerosolizedmist or cloud 822 from the outlet 816 of the apertures 814 at the secondface 806 of the aperture plate 800.

The aperture plate 800 may be mounted on an aerosol actuator 802, whichdefines an aperture 810 therethrough. This may be done in such a mannerthat the dome portion 808 of the aperture plate 800 protrudes throughthe aperture 810 of the aerosol actuator 802 and the substantiallyplanar peripheral ring portion 812 on the second face 806 of theaperture plate 800 abuts a first face 820 of the aerosol actuator 802.In another embodiment where the aperture plate 800 is substantiallyplanar, the portion of the aperture plate 800 where the apertures 814are positioned may be placed in the aperture 810 of the aerosol actuator802. A vibratory element 840 may be provided, and may be mounted on thefirst face 820 of the aerosol actuator 802, or alternatively may bemounted on an opposing second face 830 of the aerosol actuator 802. Theaperture plate 800 may be vibrated in such a manner as to draw liquidthrough the apertures 814 of the aperture plate 800 from the first face804 to the second face 806, where the liquid is expelled from theapertures 814 as a nebulized mist.

In some approaches, the aperture plate 800 may be vibrated by avibratory element 840, which may be a piezoelectric element in preferredembodiments. The vibratory element 840 may be mounted to the aerosolactuator 802, such that vibration of the vibratory element 840 may bemechanically transferred through the aerosol actuator 802 to theaperture plate 800. The vibratory element 840 may be annular, and maysurround the aperture 810 of the aerosol actuator 802, for example, in acoaxial arrangement.

In some embodiments, a circuitry 860 may provide power from a powersource. The circuitry 860 may include a switch that may be operable tovibrate the vibratory element 840 and thus the aperture plate 800, andaerosolization performed in this manner may be achieved withinmilliseconds of operation of the switch. The circuitry 860 may include acontroller 870, for example, a microprocessor, field programmable gatearray (FPGA), application specific integrated circuit (ASIC), etc., thatmay provide power to the vibratory element 840 to produce aerosolizedliquid from the aperture plate 800 within milliseconds or fractions ofmilliseconds of a signal to do so.

In some cases, the aperture plates described herein may be used innon-vibratory applications. For example, the aperture plates may be usedas a non-vibrating nozzle where liquid is forced through the apertures.As one example, the aperture plates may be used with ink jet printersthat use thermal or piezoelectric energy to force the liquid through thenozzles. The aperture plates described herein according to variousembodiments may be advantageous when used as non-vibrating nozzles withink jet printers because of their corrosive-resistant construction andpotentially finer aperture size. The aperture plates of the presentinvention may be suitable for other fluid delivery applications, such asnon-drug delivery medical applications, fuel injection, precise liquiddeposition, and other applications where aerosolization is useful, andin particular where a benefit is realized from a combination of highthroughput and small, precise droplet (particle) size. In manyapplications, the method of manufacturing apertures, as described hereinaccording to various embodiments may afford cost and/or efficiencybenefits even if precise droplet size control is not an important aspectof the produced aperture plate.

While various embodiments have been described above, it should beunderstood that they have been presented by way of example only, and notlimitation. Thus, the breadth and scope of a preferred embodiment shouldnot be limited by any of the above-described exemplary embodiments, butshould be defined only in accordance with the following claims and theirequivalents.

1-29. (canceled)
 30. A nebulizer aperture plate for use in aerosolizinga liquid in a nebulizer, comprising: a first material having a pluralityof first apertures, a second material above the first material, thesecond material having a plurality of second apertures above theplurality of first apertures in the first material; and a third materialabove the second material, the third material having a plurality ofthird apertures above the plurality of second apertures in the secondmaterial; wherein at least one of the first material, the secondmaterial, or the third material includes a characteristic of beingformed through a photolithography process.
 31. The nebulizer apertureplate of claim 30, wherein the third material is formed through aphotolithography process comprising depositing the third material arounda third patterned photolithography mask having a negative pattern to adesired aperture pattern in the third material.
 32. The nebulizeraperture plate of claim 31, wherein the third patterned photolithographymask is formed above a second patterned photolithography mask above afirst patterned photolithography mask on a releasable seed layerdeposited above a substrate.
 33. The nebulizer aperture plate of claim32, wherein the first material is electroplated above exposed portionsof the releasable seed layer.
 34. The nebulizer aperture plate of claim31, wherein the third patterned photolithography mask imparts aperturesto the third material having a diameter of between 50 μm and 80 μm. 35.The nebulizer aperture plate of claim 31, wherein the third materialnear the third apertures is formed to a thickness that is independent ofa diameter of the third apertures.
 36. The nebulizer aperture plate ofclaim 31, wherein a pitch of the third apertures and a diameter of thethird apertures are chosen such that a flowrate of the aerosolizedliquid through the third apertures is controlled.
 37. The nebulizeraperture plate of claim 36, wherein a thickness of the first materialmaterial near the apertures is independent of a placement density of theapertures in the aperture pattern.
 38. The nebulizer aperture plate ofclaim 30, wherein the first material and the third material are the samematerial.
 39. The nebulizer aperture plate of claim 38, wherein thefirst material and the third material comprise at least one of: Ni, Co,Pd, Pt, and alloys thereof.
 40. A nebulizer aperture plate for use inaerosolizing a liquid in a nebulizer, comprising: a first materialhaving a plurality of first apertures, a second material above the firstmaterial, the second material having a plurality of second aperturesabove the plurality of first apertures in the first material; a thirdmaterial above the second material, the third material having aplurality of third apertures above the plurality of second apertures inthe second material; wherein at least one of the first material, thesecond material, or the third material includes a characteristic ofbeing formed through a photolithography process, and a pitch of one ormore of the first apertures is between 2 μm and 5 μm.
 41. The nebulizeraperture plate of claim 40, wherein the first material is formed througha photolithography process comprising depositing the first materialaround a first patterned photolithography mask having a negative patternto a desired aperture pattern in the first material.
 42. The nebulizeraperture plate of claim 41, wherein the first patterned photolithographymask is formed on a releasable seed layer deposited above a substrate.43. The nebulizer aperture plate of claim 42, wherein the first materialis electroplated above exposed portions of the releasable seed layer.44. The nebulizer aperture plate of claim 41, wherein the firstpatterned photolithography mask imparts apertures to the first materialhaving a diameter of between 1 μm and 5 μm.
 45. The nebulizer apertureplate of claim 41, wherein the first material near the first aperturesis formed to a thickness that is independent of a diameter of the firstapertures.
 46. A nebulizer aperture plate for use in aerosolising aliquid in a nebulizer, comprising: a first material having a pluralityof first apertures, a second material above the first material, thesecond material having a plurality of second apertures above theplurality of first apertures in the first material; a third materialabove the second material, the third material having a plurality ofthird apertures above the plurality of second apertures in the secondmaterial; wherein at least one of the first material, the secondmaterial, or the third material includes a characteristic of beingformed through a photolithography process and at least some of theplurality of first apertures are within a diameter of and equally spacedwithin at least one of the plurality of second apertures and within adiameter of at least one of the plurality of third apertures.
 47. Thenebulizer aperture plate of claim 46, wherein the first material isformed through a photolithography process comprising depositing thefirst material around a first patterned photolithography mask having anegative pattern to a desired aperture pattern in the first material.48. The nebulizer aperture plate of claim 47, wherein the firstpatterned photolithography mask imparts apertures to the first materialhaving a diameter of between 1 μm and 5 μm.
 49. The nebulizer apertureplate of claim 48, wherein the first material near the first aperturesis formed to a thickness that is independent of a diameter of the firstapertures.